ABSTRACT Tuberculosis (TB) is a human disease caused by the bacterial pathogen Mycobacterium tuberculosis (Mtb). In 2015, TB ranked above HIV/AIDs as a leading cause of death worldwide. The gene IL12RB1 regulates human resistance to TB by promoting cytokine (IL12/IL23)-dependent differentiation of nave TH cells into TH1 and TH17 effectors. TH1 and TH17 cells limit Mtb survival by activating Mtb-infected macrophages and recruiting neutrophils to infected sites. It was established >20 years ago that IL12RB1 is transcribed and translated into IL12R?1, a transmembrane receptor on the TH cell surface that binds IL12/IL23, and then complexes with secondary receptors (IL12R?2, IL23R) to activate the intracellular signaling cascades that drive TH1/TH17 differentiation. However, we recently demonstrated that IL12RB1 is also transcribed and translated into a second isoform (Isoform 2, or Iso2) that is a secreted potentiator of IL12/IL23 activity. The mechanism whereby Iso2 potentiates IL12/IL23 activity is not known. Here, we propose a research project that will both fill important gaps in our knowledge of IL12RB1 and determine the mechanism of Iso2 potentiation. This project is significant since IL12RB1 regulates multiple immune responses including TB-resistance, and innovative since it will establish a paradigm for how natural soluble cytokine receptors potentiate cytokine activity. This project is also being pursued by an investigator with demonstrated independent expertise and productivity in the field of IL12RB1-TB interactions, in an environment that is highly supportive of basic immunology research. Finally, the methods and approach we use build on our demonstrated expertise in molecular biology, immunology and the mouse TB model. There are two Specific Aims: (AIM 1) Determine the biochemical mechanism that Isoform 2 enhances IL12/IL23 signaling; (AIM 2) Determine the immunological mechanism that Isoform 2 increases TB resistance. At the end of our studies, we will have extended our basic understanding of IL12RB1 immunobiology in the context of TB, as well as generated novel proteins with potential use as an adjunct TB therapy. Since IL12RB1's influence extends beyond TB to also include autoimmunity, cancer, and atopic disease, the mechanisms we identify are relevant to these other human diseases.